The long term objectives of this proposal are to identify the role of cytotoxic T lymphocytes (CTLs), in the pathogenesis of Duchenne muscular dystrophy (DMD) using the mdx mouse as a model system. The anticipated findings will be significant in two regards: l) they will provide information on the functional importance of elevated CTL populations reported previously in DMD muscle, and 2) they will indicate the role of CTLs in currently encountered technical difficulties in myoblast transfer and adenoviral DNA delivery. The specific aims of the proposal are: 1) To determine if autologous CTLs lyse dystrophin-deficient myotubes at a higher frequency than dystrophin-containing myotubes, using conventional cytotoxicity assays; 2) To determine if factors released from mdx muscle enhance the ability of autologous CTLs to attack mdx myotubes, using cytotoxicity assays; 3) To identify if in vivo depletion of CD8+ CTLs in pre-necrotic mdx mice prevents muscle cell death, according to histological assays of necrosis; 4) To determine if muscle necrosis is reduced or absent in perforin- deficient mdx mice, using double mutant mice, deficient in dystrophin and perforin, that I will generate; 5) To determine if muscle necrosis is reduced or absent in fas- deficient mdx mice, using double mutant mice that I will generate.